Polysubstituted indan-1-ol systems for the prophylaxis or treatment of obesity

ABSTRACT

Polysubstituted indan-1-ol compounds of formula I, its physiologically acceptable salts and physiologically functional derivatives are disclosed                    
     Compositions comprising the same, methods of preparation and methods for the prophylaxis or treatment of obesity are also disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/230,353 filed Aug. 29, 2002, now U.S. Pat. No. 8,686,347 which isincorporated herein by reference in its entirety. The instantapplication takes priority from DE 10142659.3, filed Aug. 31, 2001,which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to polysubstituted indan-1-ol compounds and theirphysiologically acceptable salts and physiologically functionalderivatives for the prophylaxis or treatment of obesity.

2. Description of the Related Art

WO 97/20806 discloses cyclopentyl-substituted indan-1-ol derivatives asantiinflammatory substances.

SUMMARY OF THE INVENTION

In a preferred embodiment, the invention provides compounds which can beused for reducing weight in mammals and which are suitable forpreventing and treating obesity. The instant compounds have atherapeutically utilizable anorectic action.

In another preferred embodiment, the invention also provides apharmaceutical composition comprising an effective amount of a compoundof formula I. The pharmaceutical composition may also comprise one ormore active compounds suitable for reducing weight or for the treatmentof obesity. The instant composition may also comprise one or morecompounds suitable for treatment of other disorders.

In another preferred embodiment, the instant invention provides a methodfor treating obesity, comprising administering to a subject in needthereof, an effective amount of a compound according to formula I.

In another preferred embodiment, the instant invention provides a methodof reducing weight in a mammal, comprising administering to said mammalan effective amount of a compound of formula I.

Additional objects, features and advantages of the invention will be setforth in the description which follows, and in part, will be obviousfrom the description, or may be learned by practice of the invention.The objects, features and advantages of the invention may be realizedand obtained by means of the instrumentalities and combinationsparticularly pointed out in the appended claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention relates to compounds of the formula (I)

in which

R1, R2, R3, and R4, independently of one another, are H, F, Cl, Br, I,CN, N3, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl,O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, wherein the alkylradicals, up to seven hydrogen atoms may be replaced by fluorine;

S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, wherein the alkylradicals, up to seven hydrogen atoms may be replaced by fluorine;

NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]2,N[(C₃-C₈)-cycloalkyl]2, NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl;

SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl;SO₂—(C₁-C₆)-alkyl; NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,COO(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂;

(C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,wherein the alkyl, alkenyl and alkynyl groups one to seven hydrogenatoms may be replaced by fluorine;

or one hydrogen may be replaced by OH, OC(O)CH₃, O—CH₂—Ph, NH₂,NH—CO—CH₃ or N(COOCH₂Ph)₂;

phenyl, 1- or 2-naphthyl,

5-tetrazolyl, 1-[(C₁-C₆)-alkyl]-5-tetrazolyl,2-[(C₁-C₆)-alkyl]-5-tetrazolyl,

1-imidazolyl,

1- or 4-[1,2,4]-triazolyl,

2- or 3-thienyl,

2- or 3-furyl,

2-, 3- or 4-pyridyl,

2-, 4- or 5-oxazolyl,

3-, 4- or 5-isoxazolyl,

2-, 4- or 5-thiazolyl,

3-, 4- or 5-isothiazolyl,

where the aryl radical or heterocycle may be substituted up to two timesby

F, Cl, Br, CN,

OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl,

S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl;

COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂ and wherein the alkyl groups one toseven hydrogen atoms may be replaced by fluorine; or

R2 and R3 together form the radical —O—CH₂—O—;

X is S, SO, SO2;

Y is (CH2)p, wherein p may be 0, 1, 2 or 3;

R5 is (C₁-C₁₈)-alkyl, (C₃-C₈)-cycloalkyl,

wherein the alkyl groups up to seven hydrogen atoms may be replaced byfluorine;

(CH₂)₁₋₆—COOH, (CH₂)₁₋₆—COO—(C₁-C₆)-alkyl, (CH₂)₁₋₆—CONH₂;

CH₂—CH(NHR10)-COR11, where R10 may be H or C(O)—(C₁-C₆)-alkyl and R11may be OH, O—(C₁-C₆)-alkyl or NH₂;

phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where therings or ring systems are in each case substituted up to three times byF, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH2, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl;

SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl;NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂;

(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl groups in eachcase, one to seven hydrogen atoms may be replaced by fluorine;

R6 is (CH₂)₀₋₆—R9, (CH₂)₀₋₆—COOH, (CH₂)₀₋₆—COO—(C₁-C₆)-alkyl,(CH₂)₀₋₆₋CONH₂, (CH₂)₀₋₆—CH(NHR15)-COR16, F, Cl, Br, CN, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, (C₆-C₈)-cycloalkyl, wherein the alkyl radicals orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine;

R15 is H, C(O)—(C₁-C₆)-alkyl;

R16 is OH, O (C₁-C₆)-alkyl, NH₂,

R7 is (CH₂)₀₋₄—R12, H, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, COO(C₁-C₆)-alkyl, COO(C₃-C₈)-cycloalkyl, wherein thealkyl radicals or cycloalkyl radicals up to seven hydrogen atoms may bereplaced by fluorine;

R8 is (CH₂)₀₋₄—R14, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, wherein the alkyl or cycloalkyl radicals up to sevenhydrogen atoms may be replaced by flourine atoms;

R9, R12, R14 independently of one another are phenyl, 1- or 2-naphthyl,biphenyl, or a heterocyclic radical, where the rings or ring systems arein each case substituted up to three times by F, Cl, Br, I, CN, OH,O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂;

(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl groups in each caseone to seven hydrogen atoms may be replaced by fluorine;

and their physiologically acceptable salts.

In a preferred embodiment, the invention provides compounds of theformula I in which

R1, R2, R3, R4, independently of one another, are H, F, Cl, Br, N₃,O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl and wherein the alkyl groups one to sevenhydrogen atoms may be replaced by fluorine;

wherein each case at least one of the radicals R1, R2, R3 and R4 isdifferent from hydrogen;

X is S, SO, SO₂;

Y is (CH₂)_(p), wherein p may be 0, 1, 2 or 3;

R5 is (C₁-C₁₈)-alkyl, (C₃-C₄)-cycloalkyl, (C₆-C₈)-cycloalkyl,

wherein the alkyl groups up to seven hydrogen atoms may be replaced byfluorine;

(CH₂)₁₋₆—COOH, (CH₂)₁₋₆—COO—(C₁-C₆)-alkyl, (CH₂)₁₋₆—CONH₂;

CH₂—CH(NHR10)—COR11, where R10 may be H or C(O)—(C₁-C₆)-alkyl and R11may be OH, O—(C₁-C₆)-alkyl or NH₂;

phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where therings or ring systems are in each case substituted up to three times byF, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine;

R6 is (CH₂)₀₋₆—R9, (CH₂)₀₋₆—COOH, (CH₂)₀₋₆—COO—(C₁-C₆)-alkyl,(CH₂)₀₋₆—CONH₂, (CH₂)₀₋₆—CH(NHR15)-COR16, F, Cl, Br, CN, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, (C₆-C₈)-cycloalkyl, wherein the alkyl radicals orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine;

R15 is H, C(O)—(C₁-C₆)-alkyl;

R16 is OH, O—(C₁-C₆)-alkyl, NH₂;

R7 is (CH₂)₀₋₄—R12, H, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, COO(C₁-C₆)-alkyl, COO(C₃-C₈)-cycloalkyl, wherein thealkyl radicals or cycloalkyl radicals up to seven hydrogen atoms may bereplaced by fluorine;

R8 is (CH₂)₀₋₄—R14, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, wherein the alkyl or cycloalkyl radicals up to sevenhydrogen atoms may be replaced by fluorine atoms;

R9, R12, R14 independently of one another are

phenyl, 1- or 2-naphthyl, biphenyl, or a heterocyclic radical, where therings or ring systems are in each case substituted up to three times byF, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine;

and their physiologically acceptable salts.

In another preferred embodiment, the invention provides compounds of theformula I in which

R1, R2, R3, R4, independently of one another, are H, F, Cl, Br, N₃,O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl and wherein the alkyl groups one to sevenhydrogen atoms may be replaced by fluorine;

wherein each case at least one of the radicals R1, R2, R3 and R4 isdifferent from hydrogen;

X is SO₂;

Y is (CH₂)_(p), wherein p may be 0, 1 or 2;

R5 is (C₁-C₈)-alkyl, wherein the alkyl group up to seven hydrogen atomsmay be replaced by fluorine;

R6 is F, Cl, Br, CN, (C₁-C₈)-alkyl, wherein the alkyl group up to sevenhydrogen atoms may be replaced by fluorine;

R7 is H, (C₁-C₁₂)-alkyl, wherein the alkyl group up to seven hydrogenatoms may be replaced by fluorine;

R8 is (C₁-C₁₂)-alkyl, wherein the alkyl group up to seven hydrogen atomsmay be replaced by fluorine;

and their physiologically acceptable salts.

The invention also contemplates compounds of the formula I in the formof their racemates, racemic mixtures and pure enantiomers, and also totheir diastereomers and mixtures thereof.

The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3,R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be straight-chain orbranched.

Heterocycle or heterocyclic radical is to be understood as meaning ringsystems which, in addition to carbon, also contain heteroatoms, such as,for example, nitrogen, oxygen or sulfur. This definition furthermoreincludes ring systems in which the heterocycle or heterocyclic radicalis fused with benzene rings.

Preferred heterocycles or heterocyclic radicals are:

heteroaryls, such as

benzimidazolyl,

1-[(C₁-C₆)-alkyl]benzimidazolyl,

imidazolyl,

2- or 3-thienyl,

2- or 3-furyl,

benzoxazolyl,

benzothiazolyl,

2-, 3- or 4-pyridyl,

pyrimidinyl,

4-, 5- or 6-pyridazin-2H-yl-3-one,

4-, 5- or 6-pyridazin-2-(C₁-C₈)-alkyl-2H-yl-3-one,

2-benzyl-4-, -5- or -6-pyridazin-2H-yl-3-one,

3- or 4-pyridazinyl,

2-, 3-, 4- or 8-quinolinyl,

1-, 3- or 4-isoquinolinyl,

1-phthalazinyl,

3- or 4-cinnolinyl,

2- or 4-quinazolinyl,

2-pyrazinyl,

2-quinoxalinyl,

2-, 4- or 5-oxazolyl,

3-, 4- or 5-isoxazolyl,

2-, 4- or 5-thiazolyl,

3-, 4- or 5-isothiazolyl,

1-[(C₁-C₆)-alkyl]-2-, -4- or -5-imidazolyl,

3-, 4- or 5-pyrazolyl,

1-[(C₁-C₆)-alkyl]-3-, -4- or -5-pyrazolyl,

1- or 4-[1,2,4]triazolyl,

4- or 5-[1,2,3]triazolyl,

1-[(C₁-C₆)-alkyl]-4- or -5-[1,2,3]triazolyl,

3-, 4- or 7-indolyl,

N-[(C₁-C₆)-alkyl]-3-, -4- or -7-indolyl

2-[(C₁-C₆)-alkyl]-3(2H)-indazolyl,

1-[(C₁-C₆)-alkyl]-3(1H)-indazolyl,

5-tetrazolyl,

1-[(C₁-C₆)-alkyl]-1H-tetrazolyl,

2-[(C₁-C₆)-alkyl]-2H-tetrazolyl.

Pharmaceutically acceptable salts are particularly suitable for medicalapplications, due to their greater solubility in water compared with thestarting or base compounds. Said salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the compounds of the formula I are salts of inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,metaphosphoric acid, nitric acid, sulfonic acid, and sulfuric acid, andalso of organic acids such as, for example, acetic acid, benzenesulfonicacid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid,gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionicacid, maleic acid, malic acid, methanesulfonic acid, succinic acid,p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid,furthermore L-ascorbic acid, salicylic acid,1,2-benzisothiazol-3(2H)-one and 6-methyl-1,2,3-oxathiazin-4(3H)-one2,2-dioxide. For medicinal purposes, particular preference is given tousing the chlorine salt. Suitable pharmaceutically acceptable basicsalts are ammonium salts, alkali metal salts (such as sodium salts andpotassium salts), and alkaline earth metal salts (such as magnesiumsalts and calcium salts).

Salts having a pharmaceutically unacceptable anion are likewise includedwithin the scope of the present invention as useful intermediates forpreparing or purifying pharmaceutically acceptable salts and/or for usein nontherapeutic applications, for example in vitro applications.

The term “physiologically functional derivative” used herein relates toany physiologically acceptable derivative of an inventive compound, forexample, an ester which on administration to a mammal, for example,humans, is capable of forming (directly or directly) such a compound oran active metabolite thereof.

A further aspect of this invention is the use of prodrugs of thecompounds of the formula I. Such prodrugs may be metabolized in vivo toa compound of the formula I. These prodrugs may or may not be activethemselves.

The physiologically functional derivatives furthermore include, forexample, glucuronides, sulfuric acid esters, glycosides and ribosides.

The compounds of the formula I may also be present in variouspolymorphous forms, for example, as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds of theformula I are included within the scope of the invention and are anotheraspect of the invention.

All references to “compound(s) according to formula (I)” referhereinbelow to a compound/compounds of the formula (I) as describedabove and also to their salts, solvates and physiologically functionalderivatives as described herein.

A “subject” may be a mammal, and is preferably a human.

The amount and effective amount of a compound according to formula (I)which is required in order to attain the desired biological effectdepends on a number of factors, or example, the specific compoundselected, the intended use, the type of administration and the clinicalstate of the patient. In general, the daily dose is in the range from0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram ofbody weight, or example, 3-10 mg/kg/day. An intravenous dose can be, forexample, in the range from 0.3 mg to 1.0 mg/kg and can be administeredin a suitable manner as an infusion of 10 ng to 100 ng per kilogram perminute. Suitable infusion solutions for these purposes may contain, forexample, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg permilliliter. Individual doses may contain, for example, from 1 mg to 10 gof the active compound. Thus, ampules for injections can contain, forexample, from 1 mg to 100 mg, and orally administerable individual doseformulations such as, for example, tablets or capsules can contain, forexample, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the caseof pharmaceutically acceptable salts, the above mentioned masses relateto the mass of the benzothiazepine ion on which the salt is based. Thecompound used for the prophylaxis or therapy of the above mentionedconditions may be the compounds according to formula (I) themselves, butthey are preferably present in the form of a pharmaceutical compositiontogether with an acceptable carrier. The carrier must be naturallyacceptable, in the sense that it is compatible with the otheringredients of said composition and is not harmful to the patient'shealth. The carrier may be a solid or a liquid, or both, and ispreferably formulated with the compound as an individual dose, forexample, as a tablet which may contain from 0.05% to 95% by weight ofthe active compound. Further pharmaceutically active substances may alsobe present, including further compounds according to formula (I). Thepharmaceutical compositions of the invention may be prepared accordingto any of the known pharmaceutical methods which essentially comprisemixing the ingredients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions of the invention are those which aresuitable for oral, rectal, topical, peroral (e.g. sublingual) andparenteral (e.g. subcutaneous, intramuscular, intradermal, orintravenous) administration, although the most suitable manner ofadministration depends in each individual case on the nature andseverity of the condition to be treated and on the nature of thecompound according to formula (I) used in each case. Sugar-coatedformulations and sugar-coated delayed-release formulations are alsoincluded within the scope of the invention. Preference is given toacid-resistant and enteric formulations. Suitable enteric coatingsinclude cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate, and anionic polymers ofmethacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be presentin separate units as, for example, capsules, cachets, lozenges, ortablets, which in each case contain a particular amount of the compoundaccording to formula (I); as powders or granules; as solutions orsuspensions in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. As already mentioned, said compositions may beprepared according to any suitable pharmaceutical method which includesa step in which the active compound and the carrier (which may compriseone or more additional components) are contacted. In general, thecompositions are prepared by uniform and homogeneous mixing of theactive compound with a liquid and/or finely dispersed solid carrier,after which the product is shaped, if necessary. Thus, a tablet, forexample, may be prepared by pressing or shaping a powder or granules ofthe compound, where appropriate, with one or more additional components.Pressed tablets may be prepared by tableting the compound infree-flowing form, for example, a powder or granules, mixed, whereappropriate, with a binder, lubricant, inert diluent and/or one or moresurface active/dispersing agents in a suitable machine. Shaped tabletscan be prepared by shaping the pulverulent compound, moistened with aninert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration include lozenges which contain a compound according toformula (I) with a flavoring, usually sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administrationpreferably comprise sterile aqueous preparations of a compound accordingto formula (I) which are preferably isotonic with the blood of theintended recipient. These preparations are preferably administeredintravenously, although they may also be administered subcutaneously,intramuscularly or intradermally as an injection. Said preparations maypreferably be prepared by mixing the compound with water and renderingthe obtained solution sterile and isotonic with the blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Suitable pharmaceutical compositions for rectal administration arepreferably present as individual dose suppositories. These may beprepared by mixing a compound according to formula (I) with one or moreconventional solid carriers, for example, cocoa butter, and shaping theresulting mixture.

Suitable pharmaceutical compositions for topical application to the skinare preferably present as an ointment, cream, lotion, paste, spray,aerosol or oil. Carriers which may be used are petroleum jelly, lanolin,polyethylene glycols, alcohols, and combinations of two or more of thesesubstances. In general, the active compound is present at aconcentration of from 0.1 to 15%, for example from 0.5 to 2%, by weightof the composition.

Transdermal administration is also possible. Suitable pharmaceuticalcompositions for transdermal administration may be present as individualpatches which are suitable for long-term close contact with theepidermis of the patient. Such patches suitably contain the activecompound in an optionally buffered aqueous solution, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activecompound concentration is from approximately 1% to 35%, preferablyapproximately 3% to 15%. A particular possibility is the release of theactive compound by electrotransport or iontophoresis, as described, forexample, in Pharmaceutical Research, 2(6): 318 (1986).

The invention furthermore provides a process for preparing the compoundsof the formula I which comprises obtaining the compounds of the formulaI by proceeding according to the reaction scheme below:

To this end, compounds of the formula II,

in which R1, R2, R3 and R4 are, as defined above, converted with ahalogen, such as, for example, bromine or chlorine, into a compound ofthe formula III.

The compounds of the formula III are converted further with metal saltsof thiols of the formula H—X—Y—R5, wherein X is sulfur and Y and R5 areas defined above into compounds of the formula IV wherein X═S and R6=H.These metal salts can be employed as such or they can be generated insolution in situ from the thiol and a base, such as, for example,aqueous sodium hydroxide.

On the other hand, compounds of the formula IV wherein X═S and R6=H canbe obtained by reacting compounds of the formula II with a base, suchas, for example, lithium diisopropylamide, for example intetrahydrofuran, and with a disulfide of the formula R5-Y—X—X—Y—R5 inwhich R5 and Y are as defined above and X═S; alternatively, instead ofthe disulfide, it is also possible to use a sulfenyl chloride of theformula Cl—X—Y—R5 wherein X═S and Y and R5 are as defined above (see,for example, D. Seebach et al.; Chem. Ber. 109, 1601-1616 (1976)).

Compounds of the formula IV in which X═S and R6 is not hydrogen can beobtained, for example, as follows: compounds of the formula II aresubjected, for example, to a fluorination, an alkylation or acondensation with an aldehyde and subsequent reduction, giving compoundsof the formula VII which for their part can be converted, for exampleafter bromination, with compounds of the formula M⁺⁻X—Y—R5 wherein X═Sand Y and R5 have the meanings described above into compounds of theformula IV wherein X═S and R6 is not hydrogen.

Compounds of the formula V in which X═SO and R6 is not hydrogen can beprepared, for example, by selective oxidation of the compound of theformula IV in which X═S, using one equivalent of peroxytrifluoroaceticacid (C. G. Venier et al.; J. Org. Chem. 47, 3773 (1982)). Thepreparation of the sulfoxides from the sulfides can also be carried outusing manganese dioxide or chromic acid (D. Edwards et al.; J. Chem.Soc. 1954, 3272). Furthermore suitable for this oxidation is hydrogenperoxide in acetic anhydride (A. V. Sviridova et al.; J. Org. Chem(Russ), English Transl.; 7, 2577(1971)).

Compounds of the formula VI in which X═SO₂ and R6 is not hydrogen can beobtained by oxidation using, for example, 2KHSO₅×KHSO₄×K₂SO₄ (Oxone),either from compounds of the formula IV in which X═S and R6 is nothydrogen or from compounds of the formula V in which X═SO and R6 is nothydrogen (see, for example, M. Hudlický, Oxidations in OrganicChemistry, ACS Monograph 186, American Chemical Society, Washington,D.C., 1990).

Compounds of the formula VIII in which R8 is not hydrogen, R7 ishydrogen and X═S can be obtained, for example, by reacting compounds ofthe formula IV with a Grignard reagent. Stepwise oxidations andalkylation or acylation reactions give access to compounds of theformulae IX to XIII. Such compounds can also be obtained by employingcompounds of the formula V or VI for the Grignard reaction.

Inorganic acids suitable for forming salts are, for example: hydrohalicacids, such as hydrochloric acid and hydrobromic acid, and also sulfuricacid, phosphoric acid and amidosulfonic acid.

Organic acids suitable for salt formation which may be mentioned are,for example: formic acid, acetic acid, benzoic acid, p-toluenesulfonicacid, benzenesulfonic acid, succinic acid, fumaric acid, maleic acid,lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylicacid, isethionic acid, methanesulfonic acid, trifluoromethanesulfonicacid, 1,2-benzisothiazol-3 (2H)-one, 6-methyl-1,2,3-oxathiazin-4(3H)-one2,2-dioxide.

The examples shown below serve to illustrate the invention withoutlimiting it. The melting points or decomposition points (m.p) measuredare uncorrected and generally depend on the heating rate.

TABLE 1 Examples Formula I

Exam- ple R1 R2 R3 R4 X Y R5 R6 R7 R8 m.p. [° C.] 1 H Cl H H SO₂ — CH₃ FH CH₃ 148 [MH⁺] 2 H Cl H H SO₂ — CH₃ F H CF₃ 333.2

The compounds of the formula I are distinguished by beneficial actionson the metabolism of lipids, and they are particularly suitable forweight reduction and, after weight reduction, for maintaining a reducedweight in mammals and as anorectic agents. Accordingly, the instantcompounds are, particular useful for treating obesity by reducingweight, maintaining weight loss, and preventing obesity by, for example,preventing symptoms of weight loss.

The compounds are distinguished by their low toxicity and their few sideeffects. The compounds may be employed alone or in combination withother weight-reducing or anorectic active compounds. Further anorecticactive compounds of this kind are mentioned, for example, in the RoteListe, Chapter 01 (Arzneimittelverzeichnis für Deutschland, published byRote Liste Service GmbH, Frankfurt) under weight-reducingagents/appetite suppressants, and may also include those activecompounds which increase the energy turnover of the organism and thuslead to weight reduction or else those which influence the generalmetabolism of said organism such that increased calorie intake does notcause an enlargement of the fat depots and a normal calorie intakecauses a reduction in the fat depots of said organism. The compounds aresuitable for the prophylaxis and, in particular, for the treatment ofproblems of excess weight or obesity. The compounds are furthermoresuitable for the prophylaxis and, in particular, for the treatment oftype II diabetes, arteriosclerosis, the normalization of lipidmetabolism, and the treatment of high blood pressure.

In a further aspect of the invention, the compounds of the formula I maybe administered in combination with one or more furtherpharmacologically active substances which may be selected, for example,from the group consisting of antidiabetics, antiadipose agents,blood-pressure-lowering active compounds, lipid reducers, and activecompounds for the treatment and/or prevention of complications caused bydiabetes or associated with diabetes.

Suitable antidiabetics include insulins, amylin, GLP-1 and GLP-2derivatives such as, for example, those disclosed by Novo Nordisk A/S inWO 98/08871 and also oral hypoglycemic active compounds.

Said oral hypoglycemic active compounds preferably include sulfonylureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon receptorantagonists, GLP-1 agonists, potassium channel openers such as, forexample, those disclosed by Novo Nordisk A/S in WO 97/26265 and WO99/03861, insulin sensitizers, activators of insulin receptor kinase,inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, for example glycogenphosphorylase inhibitors, modulators of glucose uptake and glucoseelimination, lipid metabolism-modifying compounds such asantihyperlipidemic active compounds and antilipidemic active compounds,for example HMGCoA-reductase inhibitors, inhibitors of cholesteroltransport/cholesterol uptake, inhibitors of the reabsorption of bileacid or inhibitors of microsomal triglyceride transfer protein (MTP),compounds which reduce food intake, PPAR and RXR agonists and activecompounds which act on the ATP-dependent potassium channel of betacells.

In one embodiment of the present invention, the present compounds areadministered in combination with insulin.

In another embodiment, the compounds of the invention are administeredin combination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide,glibornuride or gliclazide.

In another embodiment, the compounds of the present invention areadministered in combination with a biguanide such as, for example,metformin.

In another embodiment, the compounds of the present invention areadministered in combination with a meglitinide such as, for example,repaglinide.

In yet another embodiment, the compounds of the present invention areadministered in combination with a thiazolidinedione such as, forexample, troglitazone, ciglitazone, pioglitazone, rosiglitazone or thecompounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097,in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In yet another embodiment, the compounds of the present invention areadministered in combination with a monoamine oxidase inhibitor such asdisclosed, for example, in WO 01/12176. Particularly suitable for thispurpose are[3(S),3a(S)]-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one,(R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-oneor(R)-5-(methoxymethyl)-3-[6-cyclopropylmethoxybenzofuran-3-yl]oxazolidin-2-one.

In another embodiment, the compounds of the present invention areadministered in combination with an α-glucosidase inhibitor such as, forexample, miglitol or acarbose.

In yet another embodiment, the present compounds are administered incombination with an hCNTF (human ciliary neurotrophic factor) orderivatives thereof, such as, for example, CNTF_(AX15) or modifiedCNTF_(AX15), such as disclosed, for example, in Lambert et al., PNAS 98,4652-4657.

In another embodiment, the compounds of the present invention areadministered in combination with an active compound which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide orrepaglinide.

In yet another embodiment, the compounds of the present invention areadministered in combination with an antihyperlipidemic active compoundor an antilipidemic active compound such as, for example,cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,probucol, ezetimibe or dextrothyroxine.

In another embodiment, the compounds of the present invention areadministered in combination with more than one of the aforementionedcompounds, for example in combination with a sulfonylurea and metformin,a sulfonylurea and acarbose, repaglinide and metformin, insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

Furthermore, the compounds of the invention may be administered incombination with one or more antiadipose agents or appetite-controllingactive compounds.

Such active compounds may be selected from the group consisting of CARTagonists, NPY antagonists, melanocortin 3 or 4 (MC3 or MC4) agonists,melanin-concentrating hormone (MCH) antagonists, orexin antagonists, H3agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortinagonists, β3 adrenoceptor agonists, CCK agonists, serotonin re-uptakeinhibitors, mixed serotonin and noradrenalin reuptake inhibitors, 5HTmodulators, bombesin agonists, galanin antagonists, glucocorticoidreceptor modulators, growth hormone, growth-hormone-releasing compounds,TRH agonists, uncoupling protein 2 or 3 modulators, leptin receptoragonists, leptin mimetics, dopamine agonists (bromocriptine, doprexin),lipase/amylase inhibitors, cannabinoid receptor 1 antagonists,modulators of acylation-stimulating protein (ASP), PPAR modulators, RXRmodulators or TR-β agonists.

In one embodiment of the invention, the antiadipose agent is leptin ormodified leptin.

In another embodiment, the antiadipose agent is dexamphetamine oramphetamine.

In another embodiment, the antiadipose agent is fenfluramine ordexfenfluramine.

In yet another embodiment, the antiadipose agent is sibutramine or themono- and bis-demethylated active metabolite of sibutramine.

In another embodiment, the antiadipose agent is orlistate.

In another embodiment, the antiadipose agent is mazindol,diethylpropione or phentermine.

Furthermore, the compounds of the present invention may be administeredin combination with one or more antihypertensive active compounds.Examples of antihypertensive active compounds are beta blockers such asalprenolol, atenol, timolol, pindolol, propanolol and metoprolol, ACE(angiotensin-converting enzyme) inhibitors such as, for example,benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril andrampril, calcium channel blockers such as nifedipine, felodipine,nicardipine, isradipine, nimodipine, diltiazem and verapamil, and alsoalpha-blockers such as doxazosin, urapidil, prazosin and terazosin.Furthermore, reference may be made to Remington: The Science andPractice of Pharmacy, 19th edition, Gennaro, editor, Mack PublishingCo., Easton, Pa., 1995.

It is self-evident that every suitable combination of the compounds ofthe invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances is tobe regarded as covered by the scope of protection of the presentinvention.

The following preparations serve to illustrate the invention, butwithout limiting it.

EXAMPLES Example A

Soft gelatin capsules, comprising 100 mg of active compound per capsule:

per capsule Active compound 100 mg Triglyceride mixture fractionatedfrom coconut butter 400 mg Capsule contents 500 mg

Example B

Emulsion, comprising 60 mg of active compound per 5 ml:

per 100 ml of emulsion Active compound 1.2 g Neutral oil q.s. Sodiumcarboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s. Glycerol pure0.2 to 2.0 g Flavoring q.s. Water (demineralized or distilled) to 100 ml

Example C

Rectal drug form, comprising 40 mg of active compound per suppository:

per suppository Active compound 40 mg Suppository base ad 2 mg

Example D

Tablets comprising 40 mg of active compound per tablet:

per tablet Lactose  600 mg Corn starch  300 mg Soluble starch  20 mgMagnesium stearate  40 mg 1000 mg

Example E

Coated tablets comprising 50 mg of active compound per coated tablet:

per coated tablet Active compound  50 mg Corn starch 100 mg Lactose  60mg Sec. calcium phosphate  30 mg Soluble starch  5 mg Magnesium stearate 10 mg Colloidal silica  5 mg 260 mg

Example F

The following recipes are suitable for producing the contents of hardgelatin capsules:

a) Active compound 100 mg Corn starch 300 mg 400 mg b) Active compound140 mg Lactose 180 mg Corn starch 180 mg 500 mg

Example G

Drops can be prepared according to the following recipe (100 mg ofactive compound in 1 ml=20 drops:

Active compound 10 g Methyl benzoate 0.07 g Ethyl benzoate 0.03 gEthanol 96% 5 ml Demineralized water ad 100 ml

The activity of the compounds of formula I was assayed as follows:

Biological Test Model:

The anorectic action was tested on female NMRI mice. After removal offeed for 24 hours, the preparation to be tested was administeredintraperitoneally (i.p.) or by gavage (po). The animals were housedsingly and, with free access to drinking water, they were offeredevaporated milk 30 minutes after administration of the preparation. Theconsumption of evaporated milk was determined and the general behaviorof the animals was monitored every half an hour for 7 hours. Themeasured milk consumption was compared to that of vehicle-treatedcontrol animals.

TABLE 2 Anorectic action, measured as a reduction in the cumulative milkconsumption by treated animals compared with control animals

Dose [mg/kg] Number of animals/ cumulative milk consumption by treatedanimals N/[ml] Number of animals/ cumulative milk consumption byuntreated control animals N/[ml] Reduction in cumulative milkconsumption as % of the control Example 1 30 (i.p.) 4/2.88 5/3.86 25

The table indicates that the compounds of the formula I exhibit goodanorectic action.

The preparation of some examples is described in detail below; the othercompounds of the formula I were obtained analogously:

Example 1

5-Chloro-2-fluoro-2-methanesulfonyl-1-methyl-indan-1-ol

1. 5-Chloro-2-methylsulfanylindan-1-one

0.98 g (4 M-mol) of 2-bromo-5-chloroindan-1-one and 0.42 g (6 mmol) ofsodium thiomethoxide are suspended in 5 ml of ethanol, treated in anultrasonic bath for 30 minutes and then stirred at room temperature for90 minutes. The reaction mixture is concentrated under reduced pressureand chromatographed on silica gel using toluene/ethyl acetate 10/1. Theeluates are concentrated under reduced pressure, giving 0.63 g of5-chloro-2-methylsulfanylindan-1-one of melting point 90° C.

2. 5-Chloro-2-methanesulfonylindan-1-one

0.5 g (2.35 mmol) of 5-chloro-2-methylsulfanylindan-1-one is dissolvedin 10 ml of methanol; at 0° C., a solution of 4.33 g (7.05 mmol) of2KHSO₅×KHSO₄×K₂SO₄ in 10 ml of water is added dropwise. The mixture isstirred at room temperature for 5 h; the methanol is distilled off andthe aqueous residue is extracted with dichloromethane. The organic phaseis separated off, dried over MgSO₄, filtered and concentrated underreduced pressure. This gives 0.5 g of5-chloro-2-methanesulfonylindan-1-one of melting point 197° C.

3. 5-Chloro-2-fluoro-2-methanesulfonylindan-1-one

0.734 g (3 mmol) of 5-chloro-2-methanesulfonylindan-1-one and 1.77 g (5mmol) of N-fluoro-N′-(chloromethyl)triethylenediaminebis(tetrafluoroborate) are suspended in a mixture of 2.5 ml of water and7.5 ml of acetonitrile and stirred under reflux for 4 h. The reactionmixture is cooled, concentrated under reduced pressure and purifiedchromatographically on silica gel using the mobile phasedichloromethane. This gives5-chloro-2-fluoro-2-methanesulfonylindan-1-one of melting point 150° C.

4. 5-Chloro-2-fluoro-2-methanesulfonyl-1-methylindan-1-ol

At room temperature, 260 mg (1 mmol) of5-chloro-2-fluoro-2-methanesulfonylindan-1-one are dissolved in 10 ml ofdry tetrahydrofuran, and 0.33 ml of a 3M solution of methylmagnesiumbromide in diethyl ether is added dropwise with stirring. The reactionmixture is stirred at 50° C. for 3 h. A further 0.33 ml of themethylmagnesium bromide solution is then added, and the mixture isstirred at room temperature for another hour. After the reaction hasended, the reaction mixture is diluted with ethyl acetate and extractedsuccessively with sat. ammonium chloride solution, sat. sodium bisulfitesolution, sat. sodium bicarbonate solution and sat. sodium chloridesolution. The organic phase is dried over magnesium sulfate, filteredand concentrated under reduced pressure. Chromatographic purification onsilica gel (n-heptane/ethyl acetate 60/40) gives5-chloro-2-fluoro-2-methanesulfonyl-1-methylindan-1-ol of melting point148° C.

Example 2

5-Chloro-2-fluoro-2-methanesulfonyl-1-trifluoromethylindan-1-ol

When 5-chloro-2-fluoro-2-methanesulfonylindan-1-one is, instead ofmethylmagnesium bromide, reacted with trifluoromethyltrimethylsilane andtetrabutylammonium fluoride in tetrahydrofuran,5-chloro-2-fluoro-2-methanesulfonyl-1-trifluoromethylindan-1-ol ofmolecular weight 332.7 (C₁₁H₉ClF₄SO₃); MS (ESI): 333.20 (MH⁺) isobtained.

Additional advantages, features, and modifications will be readilyapparent to those skilled in the art. Therefore, the invention in itsbroader aspects is not limited to the specific details shown anddescribed herein. Accordingly, various modifications may be made withoutdeparting from the spirit or scope of the general inventive concept asdefined bye the appended claims and their equivalents.

As used herein and in the following claims, articles such as “the”, “a”and “an” can connote the singular or plural.

All documents referred to herein are specifically incorporated herein byreference in their entireties.

The instant priority document, DE 10142659.3 filed Aug. 31, 2001 isincorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of the formula I,

in which R1, R2, R3, R4 independently of one another are H; F, Cl, Br,I, CN, N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl,O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, wherein the alkylradicals up to seven hydrogen atoms may be replaced by fluorine;S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, wherein the alkylradicals up to seven hydrogen atoms may be replaced by fluorine; NH₂,NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂,N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl, orNH—CO—(C₃-C₈)-cycloalkyl; SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl; SO₂—(C₁-C₆)-alkyl NH—SO₂—NH₂;NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, COO(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl,or (C₂-C₈)-alkynyl, wherein the alkyl, alkenyl and alkynyl groups one toseven hydrogen atoms may be replaced by fluorine; or one hydrogen may bereplaced by OH, OC(O)CH₃, O—CH₂—Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂;phenyl, 1- or 2-naphthyl, 5-tetrazolyl, 1-[(C₁-C₆)-alkyl]-5-tetrazolyl,2-[(C₁-C₆)-alkyl]-5-tetrazolyl, 1-imidazolyl, 1- or 4-[1,2,4]-triazolyl,2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, or 3-, 4- or5-isothiazolyl, where the aryl radical or heterocycle may be substitutedup to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃,O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, COOH,CO—O—(C₁-C₄)-alkyl, CO—NH₂ and wherein the alkyl groups one to sevenhydrogen atoms may be replaced by fluorine; or R2 and R3 together formthe radical —O—CH₂—O—; X is S, SO, or SO₂; Y is (CH₂)_(p), wherein p maybe 0, 1, 2 or 3; R5 is (C₁-C₁₈)-alkyl, or (C₃-C₈)-cycloalkyl, whereinthe alkyl groups up to seven hydrogen atoms may be replaced by fluorine;(CH₂)₁₋₆—COOH, (CH₂)₁₋₆—COO—(C₁-C₆)-alkyl, (CH₂)₁₋₆—CONH₂;CH₂—CH(NHR10)-COR11, where R10 may be H or C(O)—(C₁-C₆)-alkyl and R11may be OH, O—(C₁-C₆)-alkyl or NH₂; phenyl, 1- or 2-naphthyl, biphenyl ora heterocyclic radical, where the rings or ring systems are in eachcase-substituted up to three times by F, Cl, Br, I, CN, OH,O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine; R6 is (CH₂)₀₋₆—R9, (CH₂)₀₋₆—COOH, (CH₂)₀₋₆—COO—(C₁-C₆)-alkyl,(CH₂)₀₋₆—CONH₂, (CH₂)₀₆—CH(NHR15)-COR16, F, Cl, Br, CN, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein the alkyl radicals orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine; R15 is H, or C(O)—(C₁-C₆)-alkyl; R16 is OH, O—(C₁-C₆)-alkyl,or NH₂, R7 is (CH₂)₀₋₄—R12, H, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, COO(C₁-C₆)-alkyl, or COO(C₃-C₈)-cycloalkyl, whereinthe alkyl radicals or cycloalkyl radicals up to seven hydrogen atoms maybe replaced by fluorine; R8 is (CH₂)₀₋₄—R14, (C₁-C₁₂)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein the alkyl orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine atoms; R9, R12, R14 independently of one another are phenyl, 1-or 2-naphthyl, biphenyl, or a heterocyclic radical, where the rings orring systems are in each case substituted up to three times by F, Cl,Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl,NH—(C₃-C₈)-,cycloalkyl, N[(C₁-C₈)-alkyl]₂N[(C₃-C₈)-cycloalkyl]₂,NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂,SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂;NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine; and their physiologically acceptable salts.
 2. The compoundsof the formula I, as claimed in claim 1, wherein R1, R2, R3, R4independently of one another are H, F, Cl, Br, N₃, O(C₁-C₈)-alkyl, or(C₁-C₈)-alkyl and wherein the alkyl groups one to seven hydrogen atomsmay be replaced by fluorine; wherein each case at least one of theradicals R1, R2, R3 and R4 is different from hydrogen; X is S, SO, orSO₂; Y is (CH₂)_(p), wherein p may be 0, 1, 2 or 3; R5 is(C₁-C₁₈)-alkyl, (C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein thealkyl groups up to seven hydrogen atoms may be replaced by fluorine;(CH₂)₁₋₆—COOH, (CH₂)₁₋₆—COO—(C₁-C₆)-alkyl, (CH₂)₁₋₆—CONH₂;CH₂-CH(NHR10)-COR11, where R10 may be H or C(O)—(C₁-C₆)-alkyl and R11may be OH, O—(C₁-C₆)-alkyl or NH₂; phenyl, 1- or 2-naphthyl, biphenyl ora heterocyclic radical, where the rings or ring systems are in each casesubstituted up to three times by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl,O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl,NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂,NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl, SO₃H; SO₂—NH₂,SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂;NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine; R6 is (CH₂)₀₋₆—R9, (CH₂)₀₋₆—COOH, (CH₂)₀₋₆—COO—(C₁-C₆)-alkyl,(CH₂)₀₋₆—CONH₂, (CH₂)₀₋₆—CH(NHR15)-COR16, F, Cl, Br, CN, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein the alkyl radicals orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine; R15 is H, or C(O)—(C₁-C₆)-alkyl; R16 is OH, O—(C₁-C₆)-alkyl,or NH₂; R7 is (CH₂)₀₋₄—R12, H, (C₁-C₁₂)-alkyl, (C₃-C₄)-cycloalkyl,(C₆-C₈)-cycloalkyl, COO(C₁-C₆)-alkyl, or COO(C₃-C₈)-cycloalkyl, whereinthe alkyl radicals or cycloalkyl radicals up to seven hydrogen atoms maybe replaced by fluorine; R8 is (CH₂)₀₋₄—R14, (C₁-C₁₂)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein the alkyl orcycloalkyl radicals up to seven hydrogen atoms may be replaced byfluorine atoms; R9, R12, R14 independently of one another are phenyl, 1-or 2-naphthyl, biphenyl, or a heterocyclic radical, where the rings orring systems are in each case substituted up to three times by F, Cl,Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein thealkyl groups in each case one to seven hydrogen atoms may be replaced byfluorine; and their physiologically acceptable salts.
 3. The compoundsof the formula I, as claimed in claim 1, wherein R1, R2, R3, R4independently of one another are H, F, Cl, Br, N₃, O(C₁-C₈)-alkyl, or(C₁-C₈)-alkyl and wherein the alkyl groups one to seven hydrogen atomsmay be replaced by fluorine; wherein each case at least one of theradicals R1, R2, R3 and R4 is different from hydrogen; X is SO₂; Y is(CH₂)_(p), wherein p may be 0, 1 or 2; R5 is (C₁-C₈)-alkyl, wherein thealkyl group up to seven hydrogen atoms may be replaced by fluorine; R6is F, Cl, Br, CN, or (C₁-C₈)-alkyl, wherein the alkyl group up to sevenhydrogen atoms may be replaced by fluorine; R7 is H, or (C₁-C₁₂)-alkyl,wherein the alkyl group up to seven hydrogen atoms may be replaced byfluorine; R8 is (C₁-C₁₂)-alkyl, wherein the alkyl group up to sevenhydrogen atoms may be replaced by fluorine; and their physiologicallyacceptable salts.
 4. A pharmaceutical composition comprising aneffective amount of a compound of formula I as claimed in claim 1, and apharmaceutically acceptable carrier.
 5. The pharmaceutical compositionaccording to claim 4, further comprising one or more active compoundssuitable for reducing weight or for the treatment of obesity.
 6. Thepharmaceutical composition according to claim 4, further comprising oneor more of the agents selected from the group consisting of cathine,phenylpropanolamine, amfepramone, mefenorex, ephedrine, leptin,dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine,orlistat, mazindol or phentermine or their salts for preparing amedicament for reducing weight in mammals.
 7. A method for the treatingobesity, comprising administering to a subject in need thereof, aneffective amount of a compound according to formula I as claimed inclaim
 1. 8. A method of reducing weight in a mammal, comprisingadministering to said mammal an effective amount of a compound offormula I as claimed in claim
 1. 9. A method of maintaining weight loss,comprising administering to a subject in need thereof, an effectiveamount of a compound of formula I as claimed in claim
 1. 10. The methodof claim 9, further comprising administering one or more activecompounds for reducing weight in mammals.